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1.
medrxiv; 2023.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2023.05.02.23289345

ABSTRACT

Innate lymphoid cells (ILCs) are key organizers of tissue immune responses and regulate tissue development, repair, and pathology. Persistent clinical sequelae beyond 12 weeks following acute COVID-19 disease, named post-COVID syndrome (PCS), are increasingly recognized in convalescent individuals. ILCs have been associated with the severity of COVID-19 symptoms but their role in the development of PCS remains poorly defined. Here we used multiparametric immune phenotyping, finding expanded circulating ILC precursors (ILCPs) and concurrent decreased group 2 innate lymphoid cells (ILC2s) in PCS patients compared to well-matched convalescent control groups at > 3 months after infection. Patients with PCS showed elevated expression of chemokines and cytokines associated with trafficking of immune cells (CCL19/MIP-3b, FLT3-ligand), endothelial inflammation and repair (CXCL1, EGF, RANTES, IL1RA, PDGF-AA). These results define immunological parameters associated with PCS and might help find biomarkers and disease-relevant therapeutic strategies.


Subject(s)
Inflammation , COVID-19 , Perceptual Disorders
2.
medrxiv; 2021.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2021.12.16.21267937

ABSTRACT

Background: The SARS-CoV-2 pandemic demonstrated the vulnerability of our societies to aerosol transmitted pathogens. With no less than 260mio known cases and >5mio deaths, SARS-CoV-2 is a global catastrophe leading to human and economic losses unprecedented in recent history. Thus, effective methods to limit the spread of aerosol transmitted pathogens are needed. Universal masking and curfew laws are effective but no permanent solution. Methods: A mass producible LED light source emitting homogeneous parallel UV-C light was used as a light-barrier to block the spread of infectious aerosols. In an aerosol test channel, Gram-negative and Gram-positive bacteria as well as coronavirus were nebulized and inactivation rates were determined. Findings: With air speeds of 0.1ms-1 an exposure time of 1s in the UV-C light is obtained. Reduction in CFU for E. coli was >3log10 and for S. aureus ~2.8log10. Plug-forming-units of the murine coronavirus (Mouse Hepatitis Virus, MHV) were reduced by about 3log10. Interpretation: The concept of a UV-C light barrier to ward off infectious aerosols if feasible and possible with a light element as described here. Coupled with sensor based activation/deactivation, such a technology could greatly reduce the transmission rates of aerosol transmitted pathogens while not disturbing natural human behaviour. This is an interesting technology allowing a new normal in societies after/with SARS-CoV-2.


Subject(s)
Hepatitis, Viral, Human
3.
biorxiv; 2021.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2021.09.30.462420

ABSTRACT

SARS-CoV-2 Beta variant of concern (VOC) resists neutralization by major classes of antibodies from non-VOC COVID-19 patients and vaccinated individuals. Here, serum of Beta variant infected patients revealed reduced cross-neutralization of non-VOC virus. From these patients, we isolated Beta-specific and cross-reactive receptor-binding domain (RBD) antibodies. The Beta-specificity results from recruitment of novel VOC-specific clonotypes and accommodation of VOC-defining amino acids into a major non-VOC antibody class that is normally sensitive to these mutations. The Beta-elicited cross-reactive antibodies share genetic and structural features with non-VOC-elicited antibodies, including a public VH1-58 clonotype targeting the RBD ridge independent of VOC mutations. These findings advance our understanding of the antibody response to SARS-CoV-2 shaped by antigenic drift with implications for design of next-generation vaccines and therapeutics. One sentence summarySARS-CoV-2 Beta variant elicits lineage-specific antibodies and antibodies with neutralizing breadth against wild-type virus and VOCs.


Subject(s)
Infections , COVID-19
4.
medrxiv; 2021.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2021.04.27.21256133

ABSTRACT

Background: In the 2nd year of the Covid-19 pandemic, knowledge about the dynamics of the infection in the general population is still limited. Such information is essential for health planners, as many of those infected show no or only mild symptoms and thus, escape the surveillance system. We therefore aimed to describe the course of the pandemic in the Munich general population living in private households from April 2020 to January 2021. Methods: The KoCo19 baseline study took place from April to June 2020 including 5313 participants (age 14 years and above). From November 2020 to January 2021, we could again measure SARS-CoV-2 antibody status in 4,433 of the baseline participants (response 83%). Participants were offered a self-sampling kit to take a capillary blood sample (dry blood spot; DBS). Blood was analysed using the Elecsys(R) Anti-SARS-CoV-2 assay (Roche). Questionnaire information on socio-demographics and potential risk factors assessed at baseline was available for all participants. In addition, follow-up information on health-risk taking behaviour and number of personal contacts outside the household (N=2768) as well as leisure time activities (N=1263) were collected in summer 2020. Results: Weighted and adjusted (for specificity and sensitivity) SARS-CoV-2 sero-prevalence at follow-up was 3.6% (95% CI 2.9-4.3%) as compared to 1.8% (95% CI 1.3-3.4%) at baseline. 91% of those tested positive at baseline were also antibody-positive at follow-up. While sero-prevalence increased from early November 2021 to January 2021, no indication of geospatial clustering across the city of Munich was found, although cases clustered within households. Taking baseline result and time to follow-up into account, men and participants in the age group 20-34 years were at the highest risk of sero-positivity. In the sensitivity analyses, differences in health-risk taking behaviour, number of personal contacts and leisure time activities partly explained these differences. Conclusion: The number of citizens in Munich with SARS-CoV-2 antibodies was still below 5% during the 2nd wave of the pandemic. Antibodies remained present in the majority of baseline participants. Besides age and sex, potentially confounded by differences in behaviour, no major risk factors could be identified. Non-pharmaceutical public health measures are thus still important.


Subject(s)
COVID-19
5.
biorxiv; 2021.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2021.03.20.436259

ABSTRACT

The COVID-19 pandemic caused by SARS-CoV-2 has been socially and economically devastating. Despite an unprecedented research effort, effective therapeutics are still missing to limit severe disease and mortality. Using high-throughput screening, we identified acriflavine as a potent papain-like protease (PLpro) inhibitor. NMR titrations and a co-crystal structure confirm that acriflavine blocks the PLpro catalytic pocket in an unexpected binding mode. We show that the drug inhibits viral replication at nanomolar concentration in cellular models, in vivo in mice and ex vivo in human airway epithelia, with broad range activity against SARS-CoV-2 and other betacoronaviruses. Considering that acriflavine is an inexpensive drug approved in some countries, it may be immediately tested in clinical trials and play an important role during the current pandemic and future outbreaks.


Subject(s)
COVID-19
6.
medrxiv; 2021.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2021.02.19.21252080

ABSTRACT

Background Quantitative serological assays detecting response to SARS-CoV-2 infection are urgently needed to quantify immunity. This study analyzed the performance and correlation of two independent quantitative anti-S1 assays in oligo-/asymptomatic individuals from a previously characterized population-based cohort. Methods A total of 362 samples included 108 from individuals who had viral RNA detected in pharyngeal swabs, 111 negative controls and 143 samples with positive serology but not confirmed by RT-PCR. Blood plasma was tested with quantitative assays Euroimmun Anti-SARS-CoV-2 QuantiVac ELISA (IgG) (EI-S1-IgG-quant) and Roche Elecsys ® Anti-SARS-CoV-2 CoV-2 S (Ro-RBD-Ig-quant), which were compared with each other and with confirmatory tests, including wild-type virus micro-neutralization (NT) and GenScript ® cPass™. Results were analyzed using square roots R of coefficients of determination for association among continuous variables and non-parametric tests for paired comparisons. Results Quantitative anti-S1 serology correlated well with each other (96%/97% for true-positives and true-negatives, respectively). Antibody titers decreased over time (from <30 days to >240 days after initial positive RT-PCR). Agreement with GenScript-cPass was 96%/99% for true-positives and true-negatives, respectively, for Ro-RBD-Ig-quant and 93%/97% for EI-S1-IgG-quant. Ro-RBD-Ig-quant allowed a distinct separation between positive and negative values, and less non-specific reactivity compared with EI-S1-IgG-quant. Raw values (with 95% CI) ≥28.7 U/mL (22.6–36.4) for Ro-RBD-Ig-quant and ≥49.8 U/mL (43.4–57.1) for EI-S1-IgG-quant predicted virus neutralization >1:5 in 95% of cases. Conclusions Both quantitative anti-S1 assays, Ro-RBD-Ig-quant and EI-S1-IgG-quant, may replace direct neutralization assays in quantitative measurement of immune protection against SARS-CoV-2 in certain circumstances in the future. Key points Two quantitative anti-S1 assays showed similar performance and a high level of agreement with direct virus neutralization and surrogate neutralization tests, arguing for their utility in quantifying immune protection against SARS-CoV-2.


Subject(s)
COVID-19
7.
medrxiv; 2021.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2021.01.13.21249735

ABSTRACT

BackgroundSerosurveys are essential to understand SARS-CoV-2 exposure and enable population-level surveillance, but currently available tests need further in-depth evaluation. We aimed to identify testing-strategies by comparing seven seroassays in a population-based cohort. MethodsWe analysed 6,658 samples consisting of true-positives (n=193), true-negatives (n=1,091), and specimens of unknown status (n=5,374). For primary testing, we used Euroimmun-Anti-SARS-CoV-2-ELISA-IgA/IgG and Roche-Elecsys-Anti-SARS-CoV-2; and virus-neutralisation, GeneScript(R)cPass, VIRAMED-SARS-CoV-2-ViraChip(R), and Mikrogen-recomLine-SARS-CoV-2-IgG, including common-cold CoVs, for confirmatory testing. Statistical modelling generated optimised assay cut-off-thresholds. FindingsSensitivity of Euroimmun-anti-S1-IgA was 64.8%, specificity 93.3%; for Euroimmun-anti-S1-IgG, sensitivity was 77.2/79.8% (manufacturers/optimised cut-offs), specificity 98.0/97.8%; Roche-anti-N sensitivity was 85.5/88.6%, specificity 99.8/99.7%. In true-positives, mean and median titres remained stable for at least 90-120 days after RT-PCR-positivity. Of true-positives with positive RT-PCR (<30 days), 6.7% did not mount detectable seroresponses. Virus-neutralisation was 73.8% sensitive, 100.0% specific (1:10 dilution). Neutralisation surrogate tests (GeneScript(R)cPass, Mikrogen-recomLine-RBD) were >94.9% sensitive, >98.1% specific. Seasonality had limited effects; cross-reactivity with common-cold CoVs 229E and NL63 in SARS-CoV-2 true-positives was significant. ConclusionOptimised cut-offs improved test performances of several tests. Non-reactive serology in true-positives was uncommon. For epidemiological purposes, confirmatory testing with virus-neutralisation may be replaced with GeneScript(R)cPass or recomLine-RBD. Head-to-head comparisons given here aim to contribute to the refinement of testing-strategies for individual and public health use.


Subject(s)
Severe Acute Respiratory Syndrome , COVID-19
8.
ssrn; 2021.
Preprint in English | PREPRINT-SSRN | ID: ppzbmed-10.2139.ssrn.3745128

ABSTRACT

Background: Population-based studies investigating the dynamics of the SARS-CoV-2 pandemic are needed. Here, we report on baseline findings from April through June 2020 of a prospective cohort study in Munich, Germany.Methods: We drew a representative sample of 2994 private households. The 5313 participating household members 14 years and older completed questionnaires and provided blood samples. SARS-CoV-2 seropositivity was defined as Roche N pan-Ig ≥ 0·4218. We adjusted the prevalence for the sampling design, sensitivity, and specificity. We investigated risk factors for SARS-CoV-2 seropositivity and geospatial transmission patterns by generalized linear mixed models and permutation tests.Findings: Seropositivity for SARS-CoV-2 specific antibodies was 1·82% (95% confidence interval (CI) 1·28-2·37%) as compared to 0·46% PCR-positive cases officially registered in Munich. Loss of the sense of smell or taste was associated with seropositivity (odds ratio (OR) 47·4; 95% CI 7·2-307·0) and infections clustered within households. Participants suffering from respiratory allergies (OR 2·7; 95% CI 0·9-8·6) and working in high-risk jobs (OR 2·0; 95% CI 0·5-6·7) showed non-significantly increased odds for SARS-CoV-2 seropositivity.Interpretation: Applying a validated assay, we demonstrate a low SARS-CoV-2 seroprevalence in the Munich population 14 years and older towards the end of the first pandemic wave. However, we noted official sub-registration at this early stage of the pandemic.Funding: Bavarian State Ministry of Science and the Arts, University Hospital of LMU Munich, Helmholtz Centre Munich, University of Bonn, and University of Bielefeld.Declaration of Interests: FF, TF, DM, LO, and VT report grants from the Bavarian State Ministry of Science and the Arts during the conduct oft he study. TF reports grants from the University Hospital of LMU Munich, Helmholtz Center Munich, University of Bonn, University of Bielefeld, and German Ministry for Education and Research during the conduct of the study. JH reports grants from the German Federal Ministry of Education and Research during the conduct of the study. MH and AW report personal fees and non-financial support, LO and MP report non-financial support from Roche Diagnostics. MH, LO, MP, and AW report non-financial support from Euroimmun, Viramed, and Mikrogen. MH, MP, and AW report grants, non-financial support, and other from German Center for Infection Research (DZIF). FF, MH, LO, MP, VT, and AW report grants and non-financial support from the Government of Bavaria. MH, LO, MP, and AW report non-financial support from BMW, Mercedes Benz, Munich Police, and Accenture. MH and AW report personal fees and non-financial support from Dr. Box Betrobox during the conduct of the study. LO and MP report non-financial support from Dr. Box Betrobox. MH and AW have a patent Sample System for Sputum Diagnostics of SARS-CoV-2 pending. DM reports to be a a sub-investigator on a Phase I SARS-CoV-2 vaccine trial and on a Phase I rabies vaccine trial, both sponsored by CureVac AG. MP and AW report non-financial support from Dr. Becker MVZ. VT reports support from CureVac AG outside the submitted work. AW reports personal fees and other from Haeraeus Sensors. AW reports non-financial support from Bruker Daltronics outside the submitted work. AW is involved in other different patents and companies not in relation with the serology of SARS-CoV-2. All other authors report nothing to disclose.Ethics Approval Statement: Prior to study initiation, this study had been approved by therespective Institutional Review Board.


Subject(s)
HIV Seropositivity , Myotonia Congenita , COVID-19 , Myotonic Dystrophy
9.
medrxiv; 2020.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2020.04.28.20082743

ABSTRACT

Background: The SARS-CoV-2 pandemic is leading to the global introduction of public health interventions to prevent the spread of the virus and avoid the overload of health care systems, especially for the most severely affected patients. Scientific studies to date have focused primarily on describing the clinical course of patients, identifying treatment options and developing vaccines. In Germany, as in many other regions, current tests for SARS-CoV2 are not being conducted on a representative basis and in a longitudinal design. Furthermore, knowledge about the immune status of the population is lacking. Yet these data are needed to understand the dynamics of the pandemic and to thus appropriately design and evaluate interventions. For this purpose, we recently started a prospective population-based cohort in Munich, Germany, with the aim to better understand the state and dynamics of the pandemic. Methods: In 100, randomly selected constituencies out of 755, 3,000 Munich households are identified via random route and offered enrollment into the study. All household members are asked to complete a baseline questionnaire and subjects [≥]14 years of age are asked to provide a venous blood sample of [≤]3 ml for the determination of SARS-CoV-2 IgG/IgA status. The residual plasma and the blood pellet are preserved for later genetic and molecular biological investigations. For twelve months, each household member is asked to keep a diary of daily symptoms, whereabouts and contacts via WebApp. If symptoms suggestive for COVID-19 are reported, family members, including children <14 years, are offered a pharyngeal swab taken at the Division of Infectious Diseases and Tropical Medicine, LMU University Hospital Munich, for molecular testing for SARS-CoV-2. In case of severe symptoms, participants will be transferred to a Munich hospital. For one year, the study teams re-visits the households for blood sampling every six weeks. Discussion: With the planned study we will establish a reliable epidemiological tool to improve the understanding of the spread of SARS-CoV-2 and to better assess the effectiveness of public health measures as well as their socio-economic effects. This will support policy makers in managing the epidemic based on scientific evidence.


Subject(s)
Communicable Diseases , COVID-19
10.
medrxiv; 2020.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2020.03.05.20030502

ABSTRACT

Background: In coronavirus disease 2019 (COVID-19), current case definitions presume mainly lower respiratory tract infection. However, cases seen outside the epicenter of the epidemic may differ in their overall clinical appearance due to more sensitive case finding. Methods: We studied viral load courses by RT-PCR in oro- and nasopharyngeal swabs, sputum, stool, blood, and urine in nine hospitalized cases. Infectious virus was detected by cell culture. Active replication was demonstrated by analysis of viral subgenomic replicative intermediates. Serology including neutralization testing was done to characterize immune response. Results: Seven cases had upper respiratory tract disease. Lower respiratory tract symptoms seen in two cases were limited. Clinical sensitivity of RT-PCR on swabs taken on days 1-5 of symptoms was 100%, with no differences comparing swab and sputum samples taken simultaneously. Average viral load was 6.76x10E5 copies per swab during the first 5 days. Live virus isolates were obtained from swabs during the first week of illness. Proof of active viral replication in upper respiratory tract tissues was obtained by detection of subgenomic viral RNA. Shedding of viral RNA from sputum outlasted the end of symptoms. Seroconversion occurred after about one week. Conclusions: The present study shows that COVID-19 can often present as a common cold-like illness. SARS-CoV-2 can actively replicate in the upper respiratory tract, and is shed for a prolonged time after symptoms end, including in stool. These findings suggest adjustments of current case definitions and re-evaluation of the prospects of outbreak containment.


Subject(s)
COVID-19 , Respiratory Tract Infections
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